Basic concept of Endocrine pharmacology.pptx

HORMONES AND RELATED DRUGS
Anterior Pituitary Hormones and
Thyroid Hormones and Antagonist
RISHITA D PATEL
PHARMACOLOGY DEPARTMENT
IICP

Introduction
• Hormone (Greek hormaein—to stir up) is a substance of intense biological
activity that is produced by specific cells in the body and is transported
through circulation to act on its target cells.
• Hormones regulate body functions to bring about a programmed pattern
of life events and maintain homeostasis in the face of markedly variable
external/internal environment.
14-12-2023 Rishita Patel_IICP 2

1. Pituitary
(a) Anterior
Growth hormone (GH),
Prolactin (Prl),
Adrenocorticotropic hormone (ACTH, Corticotropin),
Thyroid stimulating hormone (TSH, Thyrotropin),
Gonadotropins—Follicle stimulating hormone (FSH) and Luteinizing hormone
(LH).
(b) Posterior—Oxytocin, Antidiuretic hormone (ADH, Vasopressin).
2. Thyroid
Thyroxine (T4), Triiodothyronine (T3), Calcitonin.
3. Parathyroid
Parathormone (PTH).

4. Pancreas (Islets of Langerhans)
Insulin, Glucagon.
5. Adrenals
(a) Cortex
Glucocorticoids (hydrocortisone)
Mineralocorticoids (aldosterone)
Sex steroids (dehydroepiandrosterone)
(b) Medulla
Adrenaline, Noradrenaline
6. Gonads
Androgens (testosterone) Estrogens (estradiol) Progestins (progesterone)

Sites and mechanisms of hormone action

Sites and mechanisms of
hormone action

Anterior Pituitary Hormones

• GROWTH HORMONE (GH)
• It is a 191 amino acid, single chain peptide of MW 22000.
• Regulation of secretion The hypothalamus produces GH releasing (GHRH)
as well as release inhibitory (somatostatin) hormones. Both are peptides.
Somatostatin is also produced by D cells of islets of Langerhans in the
pancreas and by few other tissues. Receptors for GHRH and somatostatin are
G protein coupled receptors (GPCRs) which enhance or inhibit GH secretion
by increasing or decreasing cAMP formation respectively in pituitary
somatotropes.

• Somatostatin has also been shown to inhibit Ca2+ channels and open K+ channels.
• Stimuli that cause GH release are—fasting, hypoglycaemia, exercise, stress and
i.v. infusion of arginine.
• GH secretion is inhibited by rise in plasma free fatty acid levels and by high doses
of glucocorticoids.
• Dopaminergic agents cause a brief increase in GH release in normal subjects but
paradoxically depress it in acromegalics.
• IGF-1 causes feedback inhibition of GH secretion.
• Pathological involvements Excess production of GH is responsible for gigantism
in childhood and acromegaly in adults.
• Hyposecretion of GH in children results in pituitary dwarfism.
• Adult GH deficiency is rare, but when it occurs, it results in low muscle and bone
mass, lethargy, decreased work capacity, hyperlipidaemia and increased
cardiovascular risk.

Preparations and use
• The primary indication for GH is pituitary dwarfism—0.03–0.06 mg/kg
daily in the evening or on alternate days, upto the age of 20 years or more.
• Human GH produced by recombinant DNA technique (rhGH) somatropin
(191AA) is available for clinical use.
• Somatropin causes IGF-1 to appear in plasma after a delay of several hours.
IGF-1 then remains detectable for upto 48 hours.
• Early diagnosis and institution of GH therapy restores stature to near
normal.
• rhGH can also be used in Turner’s syndrome and in children with renal
failure.

• Somatropin has been tried in children with constitutional short stature ( a
person's natural height) (only if epiphyses are open) with encouraging
results.
• Commercial interests are promoting it for accelerating growth in children
without GH deficiency, but medical, ethical, cost-benefit and social
objections have been raised.
• In adult GH deficient patients, rHGH 150–300 g/day s.c. adjusted later
according to response increases lean body mass, decreases body fat,
improves energy and mentation and may reduce excess morbidity and
mortality, but stature is unaffected.

• It is now approved for AIDSrelated wasting: higher dose (0.05–
0.1 mg/kg/day) is needed. However, it should not be given to
postoperative, trauma, cancer and other critically ill patients.
• Somatropin is also being promoted for ageing, but benefits are
uncertain. Its abuse by athletes is banned, and it is one of the
drugs included in ‘dope testing’. Somatropin: NORDITROPIN 5,
10, 15 mg inj, HUMATROPE 6 mg, 12 mg cartridges, 1.33 and
5.33 mg vials.
• Adverse effects
• Somatropin has low immunogenicity; allergic reactions or
resistance to treatment are not a problem. Pain at injection site,
lipodystrophy, glucose intolerance, hypothyroidism (due to
unmasking of TSH deficiency), salt and water retention, hand
stiffness, myalgia, headache are the possible adverse effects.

GH Inhibitors
Somatostatin
• This 14 amino acid peptide inhibits the secretion of GH, prolactin, and TSH by
pituitary; insulin and glucagon by pancreas, and of almost all gastrointestinal
secretions including that of gastrin and HCl.
• The g.i. action produces steatorrhoea, diarrhoea, hypochlorhydria, dyspepsia and
nausea as side effect.
• Somatostatin constricts splanchnic, hepatic and renal blood vessels.
• The decreased g.i. mucosal blood flow can be utilized for controlling bleeding
esophageal varices and bleeding peptic ulcer, but octreotide is proffered now due to
longer duration of action.
• Its antisecretory action is beneficial in pancreatic, biliary or intestinal fistulae; can
also be used to reduce complications after pancreatic surgery.
• It also has adjuvant value in diabetic ketoacidosis (by inhibiting glucagon and GH
secretion).

• Use of somatostatin
• in acromegaly is limited by its short duration of action (t½ 2–3 min), lack of
specificity for inhibiting only GH secretion and GH rebound on
discontinuation.
• Surgical removal of pituitary adenomas is the preferred treatment
modality, but somatostatin analogues are being increasingly used.
• Dose: (for upper g.i.bleeding) 250 µg slow i.v. injection over 3 min followed
by 3 mg i.v. infusion over 12 hours.

Octreotide
• This synthetic octapeptide surrogate of somatostatin is 40
times more potent in suppressing GH secretion and longer
acting (t½ ~90 min), but only a weak inhibitor of insulin
secretion.
• It is preferred over somatostatin for acromegaly and secretory
diarrhoeas associated with carcinoid, AIDS, cancer
chemotherapy or diabetes.
• Control of diarrhoea is due to suppression of hormones which
enhance intestinal mucosal secretion.
• Dose: Initially 50–100 µg s.c. twice daily, increased upto 200
µg TDS; for acromegaly maintain with 10-30 mg i.m. of
microsphere formulation every 4 weeks.
• Adverse effects are abdominal pain, nausea, steatorrhoea,
diarrhoea, and gall stones (due to biliary stasis).
• Octreotide injected i.v. (100 µg followed by 25–50 µg/hr)
reduces hepatic blood flow and helps stop esophageal variceal
bleeding.

Lanreotide
• Another long-acting analogue of somatostatin, very
similar in actions and specificity to octreotide,
which on i.m. injection acts for 10–15 days.
• It is indicated for pharmacotherapy of acromegaly.
Pegvisomant
• This polyethylene glycol complexed mutant GH
binds to the GH receptor but does not trigger signal
transduction: acts as a GH antagonist. It is
approved for treatment of acromegaly due to small
pituitary adenomas.

PROLACTIN
• It is a 199 amino acid, single chain peptide of MW 23000; quite similar
chemically to GH.
• It was originally described as the hormone which causes secretion of milk
from crop glands of pigeon and later found to be of considerable
importance in human beings as well.
Prolactin inhibitors
Bromocriptine
• This synthetic ergot derivative 2-bromo- - ergocryptine is a potent
dopamine agonist; most of its actions are based on this property. I
• t has greater action on D2 receptors, while at certain dopamine sites in the
brain it acts as a partial agonist or antagonist of D1 receptor.
• It is also a weak alpha adrenergic blocker but not an oxytocic.

Actions
1. Decreases prolactin release from pituitary by activating dopaminergic
receptors on lactotrope cells: is a strong antigalactopoietic.
2. Increases GH release in normal individuals, but decreases the same from
pituitary tumours that cause acromegaly.
3. Has levodopa like actions in CNS—antiparkinsonian and behavioral
effects.
4. Produces nausea and vomiting by stimulating dopaminergic receptors in the
CTZ.
5. Hypotension—due to central suppression of postural reflexes and weak
peripheral a adrenergic blockade.
6. Decreases gastrointestinal motility.

• Pharmacokinetics
• Only 1/3 of an oral dose of bromocriptine is absorbed;
bioavailability is further lowered by high first pass metabolism
in liver.
• Even then, it has higher oral: parenteral activity ratio than
ergotamine. Metabolites are excreted mainly in bile. Its plasma
t½ is 3–6 hours.
• PROCTINAL, PARLODEL, SICRIPTIN, BROMOGEN 1.25
mg, 2.5 mg tabs. Uses Bromocriptine should always be started
at a low dose, 1.25 mg BD and then gradually increased till
response occurs otherwise side effects become limiting.

• USES:
1. Hyperprolactinemia due to microprolactinomas causing
galactorrhoea, amenorrhoea and infertility in women; gynaecomastia,
impotence and sterility in men.
• Bromocriptine and cabergoline are the first line drug for most cases.
• Relatively lower doses (bromocriptine 2.5–10 mg/day or cabergoline
0.25–1.0 mg twice weekly) are effective.
• Response occurs in a few weeks and serum prolactin levels fall to the
normal range; many women conceive.
• Bromocriptine should be stopped when pregnancy occurs, though no
teratogenic effect is reported.
• Most (60–75%) tumours show regression during therapy and
neurological symptoms (visual field defects, etc.) due to pressure on
optic chiasma ease. However, response is maintained only till the drug
is given— recurrences occur in many, but not all patients.

2. Acromegaly due to small pituitary tumours and inoperable cases.
Relatively higher doses are required (5–20 mg/day) and it is less effective
than octreotide/lanreotide.
Oral administration and lower cost are the advantages.
3. Parkinsonism
Bromocriptine, if used alone, is effective only at high doses (20–80 mg/day)
which produce marked side effects.
However, response is similar to that of levodopa.
It is now recommended in low dose only, as an adjunct to levodopa in
patients not adequately benefited and in those showing marked ‘on-off’
effect.

4. Diabetes mellitus (DM)
• A new use of bromocriptine based on its dopamine D2 agonistic action in the
hypothalamus has been found in type 2 DM, and it has been approved by US-
FDA as an adjunctive drug.
5. Hepatic coma: Bromocriptine may cause arousal.
6. Bromocriptine suppresses lactation and breast engorgement in case of
neonatal death, but is not recommended due to unfavourable risk: benefit ratio.
Side effects:
Side effects are frequent and dose related.
Early: Nausea, vomiting, constipation, nasal blockage. Postural hypotension
may be marked at initiation of therapy—syncope may occur if starting dose is
high. Hypotension is more likely in patients taking antihypertensives.
Late: Behavioral alterations, mental confusion, hallucinations, psychosis—are
more prominent than with levodopa.

Cabergoline
• It is a newer D2 agonist; more potent; more D2 selective and
longer acting (t½ > 60 hours) than bromocriptine; needs to
be given only twice weekly.
• Incidence of nausea and vomiting is also lower; some
patients not tolerating or not responding to bromocriptine
have been successfully treated with cabergoline.
• It is preferred for treatment of hyperprolactinemia and
acromegaly.
• Some patients who achieve total regression of prolactinoma
and normalization of prolactin levels can stop cabergoline
without recurrence. Dose: Start with 0.25 mg twice weekly;
if needed increase after every 4–8 weeks to max. of 1 mg
twice weekly.

GONADOTROPINS (Gns)
• The anterior pituitary secretes two Gns viz. FSH and LH.
• Both are glycoproteins containing 23–28% sugar and consist of two peptide
chains. The alpha-chain (92AA) is common between FSH and LH, but their
beta-chains are different: FSH (111 AA), LH (121 AA). Paradoxically the MW
of FSH (~33KD) is greater than that of LH (~30 KD), because of the sugar
moieties.
• physiological functions FSH and LH act in concert to promote gametogenesis
and secretion of gonadal hormones.
• FSH
• In the female it induces follicular growth, development of ovum and secretion
of estrogens.

• In the male it supports spermatogenesis and has a trophic influence on
seminiferous tubules.
• Ovarian and testicular atrophy occurs in the absence of FSH.
• LH
• It induces preovulatory swelling of the ripe graafian follicle and triggers
ovulation followed by luteinization of the ruptured follicle and sustains
corpus luteum till the next menstrual cycle.
• It is also probably responsible for atresia of the remaining follicles.
• Progesterone secretion occurs only under the influence of LH.
• In the male LH stimulates testosterone secretion by the interstitial cells and is
designated interstitial cell stimulating hormone (ICSH).

• Pathological involvement Disturbances of Gn secretion from pituitary may
be responsible for delayed puberty or precocious puberty both in girls and
boys.
• Inadequate Gn secretion results in amenorrhoea and sterility in women;
oligozoospermia, impotence and infertility in men.
• Excess production of Gn in adult women causes polycystic ovaries.
• Preparations
• All earlier gonadotropin preparations were administered by i.m. route.
• The newer more purified preparations can be given s.c.
• They are partly metabolized, but mainly excreted unchanged in urine: t½ 2–6
hours.

1. Menotropins (FSH + LH): is a preparation obtained
from urine of menopausal women: PREGNORM,
PERGONAL, GYNOGEN 75/150; 75 IU FSH + 75 IU
LH activity per amp, also 150 IU FSH + 150 IU LH per
amp.
2. Urofollitropin or Menotropin (pure FSH): METRODIN,
FOLGEST, FOLICULIN, PUREGON 75 IU and 150
IU per amp.
This preparation has been preferred over the combined FSH
+ LH preparation for induction of ovulation in women with
polycystic ovarian disease: these patients have elevated
LH/FSH ratio; use of FSH alone is considered
advantageous. It is also claimed to improve chances of
obtaining good quality ova for in vitro fertilization.

• 3. Human chorionic gonadotropin (HCG): is derived from urine of
pregnant women. CORION, PROFASI, PUBERGEN 1000 IU, 2000
IU, 5000 IU, 10,000 IU, all as dry powder with separate solvent for
injection.
• The foetal placenta secretes HCG which is absorbed in maternal
circulation and maintains corpus luteum of pregnancy.
• It is a glycoprotein with 33% sugar and 237 amino acids in two chains,
MW 38000.
• It is excreted in urine by the mother from which it is commercially
obtained.
• HCG binds to LH receptor with equal avidity; action of HCG is
indistinguishable from that of LH.
• Recombinant human FSH (rFSH: Follitropin alpha and follitropin beta)
and recombinant human LH (rLH: Lutropin) as well as recombinant
HCG (rHCG: Choriogonadotropin alpha) have become available.
• These are more purified. They are more expensive. Recombinant
human LH (rhLH) is marketed as LUVERIS 75 IU inj.; indications and
use is similar to HCG

Uses
1. Amenorrhoea and infertility
2. Hypogonadotrophic hypogonadism in males
3. To aid in vitro fertilization
Menotropins (FSH + LH or pure FSH) have been used to induce simultaneous
maturation of several ova and to precisely time ovulation so as to facilitate their
harvesting for in vitro fertilization.
Adverse effects and precautions
Ovarian hyperstimulation—polycystic ovary, pain in lower abdomen and even ovarian
bleeding and shock can occur in females.
Precocious puberty is a risk when given to children.
Allergic reactions have occurred and skin tests are advised.
Hormone dependent malignancies (prostate, breast) must be excluded.
Other side effects are edema, headache, mood changes.

• GONADOTROPIN RELEASING HORMONE (GnRH):
GONADORELIN
Synthetic GnRH injected i.v. (100 µg) induces prompt release of LH and FSH
followed by elevation of gonadal steroid levels.
It has a short plasma t½ (4–8 min) due to rapid enzymatic degradation; has been
used for testing pituitarygonadal axis in male as well as female hypogonadism.
Since only pulsatile exposure to GnRH induces FSH/LH secretion, while
continuous exposure desensitizes pituitary gonadotropes resulting in loss of Gn
release, therapy with GnRH or its analogues is not useful in the treatment of
hypogonadism.

• Nafarelin
This long-acting GnRH agonist is 150 times more potent than native
GnRH.
It is used as intranasal spray from which bioavailability is only 4–5%.
NASAREL 2 mg/ml soln for nasal spray; 200 µg per actuation.
Down regulation of pituitary GnRH receptors occurs in10 days but peak
inhibition of Gn release occurs at one month.
It is broken down in the body to shorter peptide segments; plasma t½ is
2–3 hours.
Uses are: Assisted reproduction: Endogenous LH surge needs to be
suppressed when controlled ovarian hyperstimulation is attempted by
exogenous FSH and LH injection, so that precisely timed mature
oocytes can be harvested. This is achieved by 400 µg BD intranasal
nafarelin, reduced to 200 µg BD when menstrual bleeding occurs.

• Uterine fibroids: Nafarelin 200 µg BD intranasal for 3–6
months can reduce the size of leiomyoma and afford
symptomatic relief.
• Endometriosis: 200 µg in alternate nostril BD for upto 6
months.
• Central precocious puberty: 800 µg BD by nasal spray;
breast and genital development is arrested in girls and
boys.
• The effect is reversible; pubertal changes resume when
therapy is discontinued.
• Adverse effects: Hot flashes, loss of libido, vaginal
dryness, osteoporosis, emotional lability.

Goserelin
• Another long-acting GnRH agonist available as a depot
s.c./i.m. injection to be used both for endogenous Gn
suppression before ovulation induction, as well as for
endometriosis, carcinoma prostate, etc.
• To achieve pituitary desensitization before ovulation
induction with exogenous Gns: 3.6 mg of the depot injection
is given once in the anterior abdominal wall 1–3 weeks
earlier.
• For endometriosis and carcinoma prostate 3.6 mg is injected
in the same way every 4 weeks or 10.8 mg is injected every 3
months.
• An androgen antagonist (bicalutamide) is given concurrently
for 3–4 weeks when goserelin is used for carcinoma prostate.

• Triptorelin:
This long acting GnRH agonist is formulated as a regular release
daily s.c. injection for short term indications, such as female
infertility, and as a depot i.m. monthly injection for long-term Gn
suppression in the treatment of carcinoma prostate, endometriosis,
precocious puberty and uterine leiomyoma.
For prostate cancer, it is combined with an androgen antagonist
flutamide or bicalutamide to prevent the initial flare up of the
tumour that occurs due to increase in Gn secretion for the first 1–
2 weeks.
Continuous treatment with any GnRH agonist is not advised
beyond 6 months due to risk of osteoporosis and other
complications.

Leuprolide
• This long acting GnRH agonist is injected s.c./i.m. daily or as a
depot injection once a month for palliation of carcinoma prostate
alongwith an androgen antagonist, as well as for other conditions
needing long term Gn suppression.
• LUPRIDE 1 mg inj., 3.75 mg depot inj., PROGTASE 1 mg/ml inj.
GnRH antagonists
• Some more extensively substituted GnRH analogues act as GnRH
receptor antagonists.
• They inhibit Gn secretion without causing initial stimulation.

• The early GnRH antagonists had the limitation of producing
reactions due to histamine release.
• Later agents like ganirelix and cetrorelix have low histamine
releasing potential and are being clinically used as s.c. inj. in
specialized centres for inhibiting LH surges during controlled
ovarian stimulation in women undergoing in vitro fertilization.
• Their advantages over long-acting GnRH agonists include:
• They produce quick Gn suppression by competitive antagonism,
need to be started only from 6th day of ovarian hyperstimulation.
• They carry a lower risk of ovarian hyperstimulation syndrome.
• They achieve more complete suppression of endogenous Gn
secretion. However, pregnancy rates are similar or may even be
lower.

ADRENOCORTICOTROPIC HORMONE (ACTH, CORTICOTROPIN)
• It is a 39 amino acid single chain peptide, MW 4500, derived from a larger
peptide pro-opio melanocortin (MW 30,000) which also gives rise to
endorphins, two lipotropins and two MSHs.
• Physiological function
• ACTH promotes steroidogenesis in adrenal cortex by stimulating cAMP
formation in cortical cells (through specific cell surface GPCRs)
• rapidly increases the availability of cholesterol for conversion to
pregnenolone which is the rate limiting step in the production of gluco,
mineralo and weakly androgenic steroids.
• Induction of steroidogenic enzymes occurs after a delay resulting in 2nd
phase ACTH action.

• The stores of adrenal steroids are very limited and rate of synthesis primarily
governs the rate of release.
• ACTH also exerts trophic influence on adrenal cortex (again through cAMP):
high doses cause hypertrophy and hyperplasia.
• Lack of ACTH results in adrenal atrophy. However, zona glomerulosa is little
affected because angiotensin II also exerts trophic influence on this layer and
sustains aldosterone secretion.
• Regulation of secretion
• Hypothalamus regulates ACTH release from pituitary through corticotropin-
releasing hormone (CRH). The CRH receptor on corticotropes is also a GPCR
which increases ACTH synthesis as well as release by raising cytosolic cAMP.
• Secretion of ACTH has a circadian rhythm.
• Peak plasma levels occur in the early morning, decrease during day and are
lowest at midnight.
• Corticosteroids exert inhibitory feedback influence on ACTH production by
acting directly on the pituitary as well as indirectly through hypothalamus.

• A variety of stressful stimuli, e.g. trauma, surgery, severe pain, anxiety, fear,
blood loss, exposure to cold, etc. generate neural impulses which converge
on median eminence to cause elaboration of CRH.
• The feedback inhibition appears to be overpowered during stress—rise in
ACTH secretion continues despite high plasma level of cortisol induced by
it.
• Arginine vasopressin (AVP) enhances the action of CRH on corticotropes
and augments ACTH release.
• AVP release and augmentation of ACTH action appears to be important
during stress.

Pathological involvement
• Excess production of ACTH from basophil pituitary tumours is responsible for
some cases of Cushing’s syndrome.
• Hypocorticism occurs in pituitary insufficiency due to low ACTH production.
• Iatrogenic suppression of ACTH secretion and pituitary adrenal axis is the most
common form of abnormality encountered currently due to the use of
pharmacological doses of glucocorticoids in nonendocrine diseases.
Use
• ACTH is used primarily for the diagnosis of disorders of pituitary adrenal axis.
Injected i.v. 25 IU causes increase in plasma cortisol if the adrenals are
functional.
• Direct assay of plasma ACTH level is now preferred. For therapeutic purposes,
ACTH does not offer any advantage over corticosteroids and is more
inconvenient, expensive as well as less predictable.

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